The long range objective of this study is to utilize "gene therapy" for treatment of bleeding disorders that are the result of missing or defective clotting factors. Gene therapy would involve genetic modification of some of a patient's somatic cells to secrete a constant supply of clotting factor to effect long-term cure of the disease. This project will develop the methodology in an animal model by using factor IX as a model gene, retroviral vectors for gene transfer, and skin fibroblasts as gene transfer recipients. The goal of the project is to demonstrate production of circulating levels of active human factor IX in animals that would be curative if achieved in human patients. Of particular concern is that the techniques developed here would be suitable for use in humans, and that there be no deleterious effects that would limit their use in humans. The specific aims involve the development of retroviral vectors for efficient gene expression, testing of various methods for reintroduction of the genetically modified fibroblasts, examination of the persistence of and continued factor IX synthesis from the reintroduced fibroblasts, and study of possible adverse effects of the procedures. It is hoped the techniques developed here will have applications to treatment of genetic diseases in general.